Design of N-acylprolyltyrosine "tripeptoid" analogues of neurotensin as potential atypical antipsychotic agents.
A series of N-acylprolyltyrosine amides was designed as tripeptoid analogues of neurotensin. The substituted dipeptides were tested in vivo for antidopamine activity by their ability to inhibit the apomorphine-induced climbing in mice and the dopamine-induced extrapolatory behavior impairment in rats. The N-acylprolyltyrosine amides structure-activity relationships have indicated the size of the N-acyl group and the configuration of amino acids that are important for the activity. We found that the bioactivity has been increased dramatically when the n-hydrocarbon chain on the N-acyl group was increased from four to five carbon atoms. The activity seems to reside exclusively in the L-Tyr diastereomers. All of the compounds tested were inactive in the cataleptogenic action and did not exhibit the acute toxicity even at doses 500-1000 times higher than ED50 in climbing test. On this basis, the N-acylprolyltyrosine amides could potentially be a novel class of atypical antipsychotic agents.
Gudasheva
T A
TA
Institute of Pharmacology, Russian Academy of Sciences, Moscow, Russia. uusolari@solaris.msk.ru
Voronina
T A
TA
Ostrovskaya
R U
RU
Zaitseva
N I
NI
Bondarenko
N A
NA
Briling
V K
VK
Asmakova
L S
LS
Rozantsev
G G
GG
Seredenin
S B
SB
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009496:Neurotensin / Q000031:analogs & derivatives*; D051381:Rats; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D014150:Antipsychotic Agents; D009496:Neurotensin; D014443:Tyrosine